1. Field of the Invention
The present invention is broadly concerned with methods for synthesizing various epothilone segments or precursors (either naturally occurring or analogs thereof) which can be used for the efficient synthesis of complete epothilones. More particularly, the invention pertains to such synthesis methods wherein, inter alia, the epothilone segment C is prepared using a unique Noyori reduction scheme, and epothilone segments B and C are connected via a novel aldol condensation reaction. These syntheses can be used to prepare the naturally occurring segments and a wide variety of corresponding analogs and homologs.
2. Description of the Prior Art
The epothilones (16-membered macrolides which were initially isolated from the myxobacterium Sorangium cellulosum) represent a class of promising anti-tumor agents, and have been found to be potent against various cancer lines, including breast cancer cell lines. These agents have the same biological mechanism of action as Taxol, an anti-cancer drug currently used as a primary therapy for the treatment of breast cancer. Other potential applications of the epothilones could be in the treatment of Alzheimer""s disease, malaria and diseases caused by gram-negative organisms. Other cancers such as ovarian, stomach, colon, head and neck and leukemia could also, potentially be treated. The epothilones also may have application in the treatment of arthritis.
In comparison to Taxol(copyright), the epothilones have the advantage of being active against drug-resistant cell lines. Drug resistance is a major problem in chemotherapy and agents such as the epothilones have overcome this problem and hold great promise as effective agents in the fight against cancer.
In addition, the poor water solubility of Taxol(copyright) has led to the formulation of this drug as a 1:1 ethanol-Cremophor concentrate. It has been determined that the various hypersensitive reactions in patients such as difficulty in breathing, itchiness of the skin and low blood-pressure are caused by the oil Cremophor used in the formulation. The epothilones are more water soluble than Taxol(copyright) which has positive implications in its formulation. Further advantages of the epothilones include easy access to multi-gram quantities through fermentation procedures. Also the epothilones are synthetically less complex, thus structural modifications for structure activity relationship studies are easily accessible.
The epothilones exhibit their activity by disrupting uncontrolled cell division (mitosis), a characteristic of cancer, by binding to organelles called microtubules that are essential for this process. Microtubules play an important role in cell replication and disturbing the dynamics of this component in the cell stops cell reproduction and the growth of the tumor. Antitumor agents that act on the microtubule cytoskeleton fall into two general groups: (1) a group that inhibits microtubule formation and depolymerizes microtubules and, (2) a group that promotes microtubule formation and stabilizes microtubules against depolymerization. The epothilones belong to the second group and have displayed cytotoxicity and antimitotic activity against various tumor cell lines.
It has been demonstrated on the basis of in vitro studies that the epothilones, especially epothilone B, are much more effective than Taxol(copyright) against multi-drug resistant cell line KBV-1. Preliminary in vivo comparisons with Taxol(copyright) in CB-17 SCID mice bearing drug-resistant human CCRF-CEM/VBL xenografts have shown that the reduction in tumor size was substantially greater with epothilone B in comparison to Taxol(copyright).
In light of the great potential of the epothilones as chemotherapeutic agents, there is a need for techniques allowing the practical, large scale, economical synthesis thereof. Furthermore, there is a need for synthesis methods which facilitate the preparation of various homologs and analogs of the known epothilones, and those having affinity labels allowing study of the binding interactions of these molecules.
The present invention overcomes the problems outlined above, and provides various practical, commercially feasible synthesis routes for the production of important epothilone precursors or segments in high yield. The invention is particularly concerned with synthesis of the precursors or segments C, D (which is a combination of segments B and C) and vinyl halide epothilone precursors.
In a first aspect of the invention, an epothilone precursor of the formula 
is synthesized using a Noyori reduction reaction. In the foregoing formula, n1 is an integer from 0-4, R4 is selected from the group consisting of H, C1-C10 straight and branched chain alkyl groups, substituted and unsubstituted benzyl groups, and C1-C10 alkoxy groups, R5 and R6 are each individually and respectively selected from the group consisting of H, substituted and unsubstituted aryl and heterocyclic groups, C1-C10 straight and branched chain alkyl groups, and substituted and unsubstituted benzyl groups, R7 is H or straight or branched chain C1-C10 alkyl groups, and Pxe2x80x2 is a protective group. The method comprises the steps of first providing a xcex2-keto ester of the formula 
where n1, R5, R6, R7 and Pxe2x80x2 are as defined above, and T is an alkyl group. This xcex2-keto ester is then preferentially hydrogenated at the C3 keto group to form the corresponding hydroxyester. This is accomplished by reacting the xcex2-keto ester with a hydrogenating agent in the presence of an asymmetric organometallic molecular catalyst comprising a metal atom or ion having one or more chiral ligands coupled thereto. The synthesis is completed by then converting the hydroxyester to the epothilone precursor.
More preferably, n1 is an integer from 0-4, R5, R6 and R7 are each individually and respectively selected from the group consisting of H and the straight and branched chain C1-C4 lower alkyls, and the protective group is benzyl. In terms of preferred process parameters, the hydrogenating agent is preferably H2 and the hydrogenating step is carried out at a pressure of from about 30-100 psi, more preferably 50-75 psi, and at a temperature of from about 40-100xc2x0 C., more preferably from about 50-75xc2x0 C. The reaction is normally allowed to proceed for a period of from about 12 hours to 5 days, and more usually for about 2-5 days. Typically, the reaction mixture is agitated during the hydrogenating step.
The catalyst used in the hydrogenation reaction is preferably one of the well-known Noyori catalysts such as RuBr2(S)-binap. However, a variety of other catalysts of this type can also be employed. The catalyst is generally used at a level of from about 1-25 mol % in the reaction mixture.
In order to complete the reaction sequence, the hydroxyester resulting from the Noyori reduction is converted to the epothilone precursor segment C. A number of routes can be used to effect this conversion. Preferably, however, the conversion involves: (1) removing the Pxe2x80x2 protecting group from the hydroxyester to form a diol; (2) protecting the oxygen atoms of the diol, forming a protected diol; (3) reducing the ester function of the protected diol to a primary alcohol; (4) oxidizing the primary alcohol to the corresponding aldehyde; (5) reacting the aldehyde with a Grignard reagent having the R4 group coupled thereto to form a secondary alcohol; and (6) oxidizing the secondary alcohol to form the final epothilone precursor.
Preferably, the Pxe2x80x2 removal step involves reacting the hydroxyester with hydrogen in the presence of a catalyst (e.g., Pd(OH)2 or Pd/C) at a pressure of from about 40-100 psi. The oxygen atom protecting step comprises reacting the diol with TBS chloride in a compatible solvent (i.e., one that will not interfere with the desired reaction) at a temperature of from about 40-100xc2x0 C. for a period of from about 30-60 hours. The ester function reduction step is preferably carried out by reacting the protected diol with the reducing agent DIBAL-H at a temperature of from about xe2x88x9220 to xe2x88x9285xc2x0 C. The oxidation of the primary alcohol is carried out most conveniently using 4-methylmorpholine N-oxide and a catalytic amount of tetrapropylammonium perruthenate. The Grignard reaction serving to attach the R4 group is entirely conventional and well within the skill of the art; likewise, the final oxidation of the secondary alcohol is trivial using the aforementioned oxidation procedure, i.e., NMO and TPAP.
In another aspect of the invention, a method is provided for the production of epothilone precursor D, which is a combination of segments B and C. Segment C is of course produced as outlined above. Segment B is of the formula 
where n2 is an integer from 1-4, and R3 is selected from the group consisting of H, C1-C10 straight and branched chain alkyl groups, substituted and unsubstituted benzyl groups, and C1-C10 alkoxy groups. This segment can be efficiently produced using known techniques.
The segments B and C are connected by first reacting the segment C precursor with a base to form an enolate, followed by reacting the enolate with the segment B. These reactions are generally carried out by initially cooling the base to a temperature of about xe2x88x9275xc2x0 C., adding the segment C precursor and elevating the temperature of the mixture to about xe2x88x9240xc2x0 C., then recooling the mixture to at least about xe2x88x9275xc2x0 C. and adding the precursor segment B thereto.
The invention also is concerned with a method of synthesizing vinyl halide epothilone precursors having the general formula 
where n3 is an integer from 1-4, R is selected from the group consisting of C4-C8 cycloalkyl, and substituted and unsubstituted aromatic and heteroaromatic groups, R1 and R2 are each individually and respectively selected from the group consisting of H, C1-C10 straight and branched chain alkyl groups, substituted and unsubstituted benzyl groups, and C1-C10 alkoxy groups, Pxe2x80x2 is a protecting group, and M is either bromine or iodine. This reaction involves first providing an alkynyl ketone of the formula 
wherein n3 and Pxe2x80x2 are as previously defined. Thereafter, the alkynyl ketone is asymmetrically reduced to create the alcohol form of the alkynyl ketone. This alcohol form is then reacted with a reagent system selected from the group consisting of (R1)3Al and zirconocene dichloride or stannyl cupration reagent and R1-halide to form a vinyl metal species. The vinyl metal species is then reacted with an aryl or vinyl halide to form an allyl alcohol. This allyl alcohol is then converted to the vinyl halide epothilone precursor.
Normally, the asymmetric reduction step involves creating the reduced form of the alkynyl ketone and the resulting alcohol is protected using TBS as a protecting agent. The R1-halide is selected from the group consisting of R1Br and R1I. The conversion step preferably includes the step of initially converting the allyl alcohol to an alkynyl stannane, reducing the stannane with chlorohydridozirconocene to form a 1,1-dimetallo Zr-Sn species. The dimetallo species is then hydrated to form a vinyl stannane, which is then quenched with either iodine or bromine. Alternately, the conversion step may be accomplished by transmetallating the dimetallo species with an organocuprate, quenching with an alkyl-R2-OTf, and final quenching with either iodine or bromine incorporating the R2 group.
The molecular architecture of representative epothilones (Formulae A-B) reveals three essential domains. These include the two chiral domains, namely the C1-C8 polypropionate region and the C12-C15 region, and the achiral spacer C9-C11 which unites the chiral domains. Additional structural features include a thiazole moiety, the C16 double bond, a methyl group at C4 and a cis-epoxide moiety (C12-C13) in the epothilones of Formula A. In the following formulae A and B, n1 is an integer from 0-4, n2 and n3 are each respectively integers from 1-4, R is selected from the group consisting of C4-C8 cycloalkyl, and substituted and unsubstituted aromatic and heteroaromatic groups, R1, R2, R3 and R4 are each individually and respectively selected from the group consisting of H, C1-C10 straight and branched chain alkyl groups, substituted and unsubstituted benzyl groups, and C1-C10 alkoxy groups, R5 and R6 are each individually and respectively selected from the group consisting of H, substituted and unsubstituted aryl and heterocyclic groups, C1-C10 straight and branched chain alkyl groups, and substituted and unsubstituted benzyl groups, R7 is H, or straight or branched chain C1-C10 alkyl groups, X is either oxygen or NH, and Y is either oxygen or H2. 
Scheme 1 below outlines a retrosynthetic analysis respecting the total synthesis of the epothilones of Formula A in accordance with the invention, where each n1 and n2 equal 1, R is 2-methyl-thiazol-4-yl, R1 is methyl, R2 is H or methyl, R3, R4, R5 and R6 are methyl, R7 is H, and X and Y are oxygen. Standard epoxidation and macrolactonization strategies are used for the formation of the C12-C13 epoxide moiety and the 16-membered macrolide. The analysis for other analog epothilones of Formula A is identical, and also for the epothilones of Formula B and its analogs, with the epoxidation step being omitted. Included among the novel features of this synthesis are the following:
A novel route to the C1-C6 segment labeled C in Scheme 1 that utilizes a stereoselective hydrogenation reaction, i.e., a Noyori reduction.
A novel connection of segments C and the C7-C11 segment B utilizing a diastereoselective aldol reaction that renders the required diastereomer.
A novel route to the C12-C20 segment A which provides maximum control over the geometries of the two double bonds i.e., C12-C13 and the C16-C17 double bond. This is achieved by using stereo- and regioselective hydro/carbo-metalation reactions starting from alkyne precursors. 
The synthesis of segment C has been accomplished via two unique and complementary routes, detailed in Schemes 2 and 3 below, which illustrates the synthesis of the naturally occurring segment C. A novel step in the synthesis of the C1-C6 segment utilizes the Noyori hydrogenation of xcex2-keto ester 4 to generate the requisite stereochemistry at C3. This Noyori hydrogenation (Noyori, R. et al., in Asymmetric Hydrogenation of xcex2-Keto Carboxylic Esters. A Practical, Purely Chemical Access to xcex2-Hydroxy Esters in High Enantiomeric Excess, 109 J. Am. Chem. Soc. 5856-5858 (1987)) provides the required enantiomer with high selectivities (92-95% enantiomeric excess). The use of a Noyori hydrogenation reaction permits large, commercial scale production of segment C.
The required xcex2-keto ester 4 is obtained in two steps from the readily available starting material 3-benzyloxypropionic acid (2). Asymmetric hydrogenation of 4 in methanol using RuBr2(S)-binap as catalyst at 60 psi gives the xcex2-hydroxyester 5 in 71-85% yield (92-95% ee). Deprotection of the benzyl ether and bis-silylation of the resultant diol 6 provides ester 7. The ester is reduced to the known primary alcohol 8 using DIBAL-H. The alcohol is then oxidized to the known aldehyde 9 using a previously unreported oxidation procedure. The aldehyde is then reacted with EtMgBr using a reported procedure (Claus, et al., Synthesis of the C1-C9 Segment of Epothilons, Tetrahedron Lett., 38:1359-1362 (1997)) to give the known secondary alcohol 10 in 65% yield. This alcohol is then oxidized to the C1-C6 segment C using TPAP and NMO.
In summary, although segment C is a key synthon in previously reported total syntheses (Nicolaou, et al., Total Syntheses of Epothilones A and B via a Macrolactonization-Based Strategy, J. Am. Chem. Soc., 119:7974-7991 (1997)) of the epothilones, the synthetic route utilizing the asymmetric Noyori hydrogenation is unique.
The alternate route toward segment C allows for the introduction of affinity labels and modifications at the C4 position as shown in Scheme 3. Applying the Noyori reduction to the known unsubstituted xcex2-keto ester 11 provides a building block that can be used for the modifications at C4 of the epothilones. This Scheme accordingly allows for modification of the epothilones and gives a more general route to introduce a variety of substituents at this position.
Thus, the Noyori hydrogenation of xcex2-keto ester 11 yields the known xcex2-hydroxy ester 12 (Ali, et al., Formal Syntheses of Cryptophycin 1 and Arenastatin A, Tetrahedron Lett., 38:1703-1706 (1997)) in 97% yield (in 97% enantiomeric excess). The Frater alkylation of xcex2-hydroxy ester 12 yields the previously reported xcex1-methyl analogue 13 (Ali, et al., Formal Syntheses of Cryptophycin 1 and Arenastatin A, Tetrahedron Lett., 38:1703-1706 (1997)) in 71% yield (98% diastereomeric excess). A second Frater alkylation of hydroxy ester 13 gave bis-dimethyl derivative 5 in 59% yield which was then converted to epothilone segment C by the chemistry shown in Scheme 2. At this stage, other substituents such as benzyl, allyl and other C1-C6 alkyl groups can be introduced by using other electrophiles in the second Frater alkylation in place of iodomethane. The novel aspect about this alternate route to segment C is the ability to alter the substituents at the C4 position of the epothilones using the aforementioned Frater alkylation strategy. 
The invention makes it possible to synthesize several analogs of segment C with various chain elongations and/or substitutions at C2 and substitutions at the xcex1-carbon relative to the keto group. It also allows for, as mentioned before, modifications at the carbon atom between the keto and the protected secondary hydroxy group with other groups. These chain extensions and substitutions are illustrated by a general Formula C, wherein n1 is as defined above, R5, R6 and R7 are as defined previously, and Pxe2x80x2 is a protecting group, especially TBS or p-methoxybenzylidene acetal. The synthesis of these modified derivatives can be achieved utilizing chemistry exemplified in the synthesis of segment C in Schemes 2 and 3 respectively. These modified segments can then be utilized in the total synthesis of various analogs of epothilones. 
The synthesis of the C7-C11 segment B is preferably achieved using previously. reported chemistry (Lin, Efficient Total Syntheses of Pumiliotoxins A and B, Applications of Iodide-Promoted Iminium Ion -Alkyne Cyclization in Alkaloid Construction, J. Am. Chem. Soc., 118:9062-9072 (1996)) and is outlined in exemplary Scheme 4, which is precursor of a naturally occurring epothilone. 
This synthesis can also be used to introduce various chain-elongations on this segment and to introduce various other substituents at C-8. These modifications can be illustrated by Formula D, wherein n1 and R3 are as defined previously. Their synthesis can be achieved using chemistry exemplified in the synthesis of segment B in Scheme 4. Again, these modified segments can then be utilized in the total synthesis of various analogs of epothilones. 
The connection of the two segments C and B utilizes a highly diastereoselective aldol reaction, exemplified in Scheme 5 showing the connection of the two precursors B and C of a naturally occurring epothilone. When the C1-C6 ketone segment C is treated with a base, for example lithium diisopropylamide and the resultant enolate reacted with C7-C11 aldehyde segment B, a single desired diastereomer 14 was observed in 21% yield (unoptimized). This diastereselectivity is believed to arise from a favorable nonbonding interaction between the C10-C11 double bond and the carbonyl group of the aldehyde that gives rise to the desired diastereomer. After the connection is made, the resultant secondary alcohol is protected as the corresponding tert-butyldimethylsilyl ether.
Similar chemistries would apply for the connection of modified segments C and B of the type discussed previously and emplified by Formulae C and D. 
The invention also provides a new route to the C12-C20 segment (segment A of the naturally occurring epothilone), and corresponding analogs thereof. This involves new ways to set the C16-C17 trisubstituted double bond and the C12-C13 cis-double bond, which serves as precursor to the cis-epoxide at C12-C13 in the epothilones.
The introduction of the thiazole moiety draws upon zirconium-catalyzed carboalumination chemistry (Wipf, Rapid Carboalumination of Alkynes in the Presence of Water, Agnew. Chem., Int. Ed. Engl., 32:1068-1071 (1993)) wherein a C16-C17 alkyne bond in an appropriately functionalized C13-C17 propargylic alcohol 16 (Scheme 6) is subjected to methylalumination in the presence of zirconocene dichloride (Cp2ZrCl2). The resultant alkenylalane is coupled with 2-methyl4-bromothiazole 17 in the presence of zinc chloride under Pd(0) catalysis to access the trisubstituted E-olefin 19 stereoselectively following the protection of the alcohol 18 as the OTBS-ether.
The chiral propargylic alcohol 16 is obtained via the asymmetric reduction of the readily available alkynyl ketone 15. This is exemplified in Scheme 6, which illustrates the synthesis of the precursor for the naturally occurring epothilone. After the introduction of the thiazole moiety, the known primary alcohol 21 is revealed by deprotection of the PMB ether 19 and then oxidized to the previously reported (Mulzer, J., et al. Easy Access to the Epothilone Familyxe2x80x94Synthesis of Epothilone B, Tetrahedron Lett., 39:8633-8636 (1998)), C13-C20 aldehyde 22.
Alternately, a stannylcupration-methylation methodology (Harris, et al., Synthetic Approaches to Rapamycin. 3. Synthesis of a C1-C21 Fragment, Synlett, pp. 903-905 (1996)) can be used in order to introduce the trisubstituted olefin. Thus the O-TBS ether 16a (Scheme 7) of propargylic alcohol 16 on treatment with the starnylcup-rate reagent 20 followed by methylation with iodomethane provides the corresponding stannane which is then coupled under Stille conditions with the bromothiazole 17 to yield the olefin 19.
The synthesis of 2-methyl-4-bromothiazole 17 from the known 2,4-dibromothiazole (Reynaud, et al., Sur une Nouvelle Synthese du Cycle Thiazolique, Bull. Soc. Chim. Fr., 295:1735-1738(1962)) is outlined in Scheme 8.
The zirconium-catalyzed methylalumination strategy constitutes a novel route to construct the C16-C17 double bond and to introduce the thiazole ring. The novelty lies in the use of a chiral propargylic alcohol like 16 in the carbometalation reaction followed by the direct introduction of the thiazole unit.
This methodology also allows for the introduction of various substituents and chain elongations on the C12-C20 segment A. Thus starting with analogs of the ketone 15 in Scheme 6, a variety of chain-elongated derivatives of segment A can be produced. Also carrying out an ethylalumination (Et3Al) in place of methylalumination (AlMe3) (Scheme 6) allows the introduction of an ethyl group (Et) at C16. In the same context, other groups can also be introduced using the alternate stannylcupration-alkylation method by replacing iodomethane with other electrophiles in this reaction shown in Scheme 7. In addition, the thiazole ring can be replaced by other cyclic, aromatic and heteroaromatic rings by using other vinyl or aromatic/heteroaromatic halides in place of 2-methyl-4-bromothiazole 17 in the coupling reaction following either the carboalumination or stannylcupration strategy exemplified in Schemes 6 and 7 respectively.
The goals in the construction of the C12-C13 Z-olefinic, were to design a method providing maximum control over the olefin geometry and to furnish common intermediates in the synthesis of both epothilones A and B. The introduction of affinity labels at C-12 was also a consideration.
The C12-C13 olefin can be constructed in the form of Z-vinyl iodides I that can be obtained from vinylstannanes with defined configurations. The vinyl stannanes will be accessed by using known chemistry reported by Lipshutz et al., Preparation of Z-Vinylstannanes via Hydrozirconation of Stannylacetylenes, Tetrahedron Lett., 33:5861-5864 (1992); Lipshutz, et al., Hydrozirconation/Transmetalation of Acetylenic Stannanes. New 1,1-Dimetallo Reagents, Inorganica Chimica Acta, 220:41-44 (1994), which utilizes a 1,1-dimetallo species as a stereodefined 1,1-vinyl dianion synthon. An exemplary synthesis is given in Scheme 9, for the precursor to a naturally occurring epothilone, and starts with a Corey-Fuchs reaction (PPh3, CBr4) of the known aldehyde 22, followed by base-induced elimination and quenching of the lithium acetylide with tributyltin chloride (Bu3SnCl) to yield alkynylstannane 23. The 1,1-dimetallo species 24 is generated by hydrozirconation of the alkynyl stannane 23 using chlorohydridozirconocene (Schwartz reagent). An aqueous quench would provide Z-vinylstannane 25a or alternatively, selective transmetalation with a higher order cuprate, followed by addition of an electrophile (MeOTf in case of epothilone B) to the resultant species provides the xcex1-substituted vinylstannane 25b with high stereoselectivity. The Z-vinylstannanes 25a and 25b can then be transformed to the corresponding vinyl iodides I utilizing iodine with retention of configuration. 
An alternative route to the synthesis of alkynylstannane 23 (Scheme 9a) which would allow for incorporation of different substituents at the C16 carbon involves the asymmetric epoxidation of secondary alcohol 18a under the Sharpless conditions using (xe2x88x92)-diisopropyl tartrate, tert-butyl hydroperoxide and titanium isopropoxide to give epoxide 19a. The alcohol function on the epoxide can be oxidized with TPAP, NMO to give ketone 20a which can be reacted with Wittig reagents containing thiazole or other aromatic/heteroaromatic rings to give the corresponding trans-olefins. The terminal epoxide in this olefin can then be opened with trimethylsilyl acetylide to give secondary alcohol 22a. The trimethylsilyl group can then be substituted for a trialkyl stannyl group on treatment of 22a with TBAF and bis-tributyltin oxide and the obtained product treated with TBSCl to give compound 23.
The foregoing chemistries can be used for the synthesis of analog precursors as well. Such analogs are best illustrated by Formula E, wherein n3, R, R1 and R2 are as defied previously. Again all of these modified segments can then be utilized in the total synthesis of various analogs of epothilones.
In summary, although the vinyl iodides E are previously reported (20,21) compounds, the method to synthesize it from the known aldehyde 22 is different from conditions reported in other total syntheses of epothilones. In addition, the above mentioned hydrozirconation reactions provide precise control over the geometry of the C12-C13 olefin bond. Also the use of other electrophiles in the transmetalation reaction with the intermediate species 24 allows for the synthesis of various analogs. 
Two other epothilone derivatives of special interest may be synthesized in accordance with the invention. In one such derivative the lactone functional group is replaced with an ether functionality and in the other a lactam functionality is used in lieu of the lactone functional group. Thus in the first derivative, and referring to Formula A, X is O, Y is H2, n1, n2, and n3 are 1, R is 2-methyl-thiazol-4-yl, R1 is methyl, R2 is H or methyl, and R3, R4, R5 and R6 are methyl. In the second derivative, the only change is that X is NH and Y is O. These could be synthesized by the reaction sequences shown in Schemes 10 and 11. Thus selective deprotection at C1 by camphorsulfonic acid (CSA) (Scheme 10), formation of the mesylate derivative of the corresponding primary alcohol, selective deprotection of the C15 TBS ether and base-induced cyclic ether formation should provide compounds 26xe2x80x2. Again, the final stages in the synthesis would involve the deprotection of both the TBS groups from the macrolides (TFA, CH2Cl2) and the diastereoselective epoxidation of the C12-C13 double bond with epoxidizing agents such as dimethyldioxirane to give the ether derivatives 29 and 30.
For the lactam formation (Scheme 11) again compound 26 could be selectively deprotected at C-1 followed by sequential oxidation of the primary alcohol first under Swern conditions followed by NaClO2-NaH2PO4 would furnish the known acids. These known acids can be converted to their allyl esters and then the TBS ether at C15 can be deprotected selectively. Mitsunobu inversion of these alcohols and azide formation via the corresponding mesylates will provide the azides with the correct stereochemistry at C15. Reduction of the azides (PPh3, H2O) followed by salt formation of the amine will provide 32. Deprotection of the allyl esters (Pd(PPh3)4, base) followed by macrolactamization (HBTU) will provide the lactams 33. Again, deprotection of both the TBS groups from the macrolides (TFA, CH2Cl2) and the diastereoselective epoxidation of the C12-C13 double bond with epoxidizing agents such as dimethyldioxirane would give the lactam derivatives 34 and 35.
Representative C4-C8 cycloalkyl, substituted and unsubstituted aromatic and heteroaromatic groups, C1-C10 straight and branched chain alkyl groups, substituted and unsubstituted benzyl groups, C1-C10 alkoxy groups, and heterocyclic groups useful in the formation of epothilone analogs are set forth below.
C4-C8 cycloalkyl groups: cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
Substituted and unsubstituted aromatic groups: phenyl, phenyl groups substituted at any position with C1-C4 straight or branched chain alkyls, C1-C4 alkoxy groups, halogens, amines, amides, azides, sulfides, carboxylic acids and their derivatives, and hydroxides.
Substituted and unsubstituted heteroaromatic groups: thiazoles, pyrroles, furans, thiophenes, oxazoles and pyrridines, and imidazoles.
C1-C10 straight and branched chain alkyl groups: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, isopentyl, octyl, nonyl, and t-butyl.
Substituted and unsubstituted benzyl groups: benzyl, benzyl groups substituted at any position with C1-C4 straight or branched chain allyls, C1-C4 alkoxy groups, halogens, amines, amides, azides, sulfides, carboxylic acids and their derivatives, and hydroxides.
C1-C10 alkoxy groups: methoxy, ethoxy, propoxy, butoxy, isopropoxy, t-butoxy, and nonoxy.
Heterocyclic groups: piperidines, furans, pyrroles, oxazolines, and thiophenes.
The following examples set forth various syntheses of the type described previously. It is to be understood, however, that these examples are provided by way of illustration and nothing therein should be taken as a limitation upon the overall scope of the invention.